It is now quite clear that a subset of patients with metastatic melanoma treated with CTLA-4 blocking antibodies have durable clinical benefit. The experience of our group and others leads us to several vital questions which require answers so that more patients may benefit. The preliminary data show that patients with pre-existing or induced immunity to NY-ESO-1 have a higher likelihood of clinical benefit. Validation of this observation in the large population of patients treated on a randomized trial in the adjuvant setting will further inform us of the importance of NY-ESO-1 immunity. If our initial observations are confirmed, that knowledge could lead to two impactful moves: (1) prospective identification of patients with pre-existing antibodies for up-front treatment with this and other immunotherapies and (2) incorporation of NY-ESO-1 vaccines into treatment programs for patients with no pre-existing immunity. Outside of the area of immunotherapy, this study will be the largest survey of NY-ESO-1 immunity in patients at the stage III to IV transition. The prognostic importance of sero-status in the adjuvant setting will be determined by our work. Further, the proposed analysis of patients treated with ipilimumab alone or in combination with chemotherapy will be highly significant as this and other immunotherapeutics move toward standard use. Knowledge of how chemotherapy may augment or detract from the immunologic effects of CTLA-4 blockade will inform the field concerning rational combination therapies. PUBLIC HEALTH RELEVANCE: Preliminary data show that patients with pre-existing or induced immunity to NY-ESO-1 have a higher likelihood of clinical benefit. Validation of this observation in the large population of patients treated on a randomized trial in the adjuvant setting will further inform us of the importance of NY-ESO-1 immunity.